Hyperproliferative disorders, such as cancer, are associated with the growth of abnormal, or neoplastic cells. In cancer, this uncontrolled cellular proliferation will often result in unregulated growth of malignant tissue and invasion of adjacent or local cells. Eventually, the malignant cells spread, or metastasize, to lymph nodes or remote areas by traveling through the blood or lymphatic system. Moreover, these abnormal cells are often able to proliferate under conditions where a normal cell would not grow.
Although the etiology of cancer has not been clearly defined, numerous mechanisms and processes have been implicated in disease onset and progression, including both environmental and genetic factors. However, cancer pathogenesis ultimately results from DNA mutations that impact cell growth, differentiation, and/or survival.
Cancer encompasses a broad group of medical conditions and syndromes, and can manifest in almost any organ and/or tissue in the body. As a result, there are many types of cancer, for example, bladder, breast, cervical, colon, hematologic, lung, ovarian, pancreatic, prostate, renal cell, and testicular. Moreover, cancer can present in any age, in many forms, and with varying degrees of invasiveness and aggressiveness.
Traditionally, treatments for cancer have involved surgery, radiation and chemotherapy. Depending on the type and location of the cancer, surgery can be an option for certain patients. Surgery is often a radical step and can invariably carry serious risks for the patient. In addition to surgical complications, there always exists the risk the entire cancer cannot be removed. Radiation therapy involves the use of ionizing radiation to kill cancer cells. Although radiation therapy is effective in killing cancer cells, it carries the risk of concurrently damaging non-cancerous cells. Higher and frequent radiation dosing can have long-term risks, such as secondary malignancies and reproductive effects. Chemotherapy involves administering cytotoxic drugs to the patient, often in a regimen involving a combination of such drugs. While chemotherapy is effective in killing cancer cells, it also harms normal cells that divide rapidly, leading to adverse side effects such as myelosuppression. Chemotherapy is often accompanied by additional side effects, such as severe nausea/vomiting and organ specific toxicities, which can force premature discontinuation of treatment.
Most recently, research has focused on identifying specific cellular targets for therapies. Unlike standard chemotherapy, targeted therapies are designed to only interact with specific molecular targets involved in the pathways and processes. These pathways and processes are used by cancer cells to grow, divide, and spread throughout the body. In the body, tyrosine kinases (TKs) are known to phosphorylate specific tyrosyl residues in specific proteins involved in regulating cell proliferation and differentiation. Unregulated activation of such kinases, resulting from genetic abnormalities (e.g. point mutations; translocation and genomic amplification) in the genes that encode these proteins, can result in unregulated cell growth. For example, BCR-ABL tyrosine kinase (BCR-ABL TK) has been known to activate many pro-growth and cell survival mechanisms, which in turn promote cell proliferation and survival, and contribute to BCR-ABL mediated leukemic transformation of bone marrow progenitor cells. Therefore, BCR-ABL TK-specific inhibition has been the focus of significant drug discovery efforts. BCR-ABL TK-specific inhibitors (BCR-ABL TKIs), such as imatinib, can bind and stabilize the inactive conformation, and have been successful in maintaining certain chronic myelongenous leukemias (CML) in remission to a controlled chronic condition.
However, BCR-ABL TKIs have failed to produce a similar long-term response in related leukemias, such as pediatric and adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). While current BCR-ABL-targeted drugs appear to kill Ph+ ALL cells in vitro, these drugs fail to meaningfully maintain low levels of leukemia burden in patients with Ph+ ALL, invariably leading to relapse and poor long-term outcomes. Additionally, such therapy also fails to eradicate persistent disease in patients with either Ph+ ALL or CML. Although additional chemotherapy and/or hematopoietic stem cell transplantation (HSCT) can improve the remission rate for some Ph+ ALL patients, relapses remain common, with an 18- to 24-month survival rate of 64% and an even worse relapse-free survival rate.
Resistance to BCR-ABL TKIs is believed to contribute to the inability to induce adequate clinical responses. A major mechanism of BCR-ABL TKI resistance is thought to relate to mutations that result in the interference of drug binding to the BCR-ABL kinase domain. BCR-ABL mutations confer different levels of resistance, ranging from concentration dependent resistance to complete BCR-ABL TKI resistance. The most clinically significant BCR-ABL kinase domain (KD) mutations are P-loop mutations and the T315I mutation. Significantly, the T315I mutation produces the most common and highest form of resistance of any mutation, resulting in resistance to both imatinib and second generation BCR-ABL TKIs, dasatinib and nilotinib. Nevertheless, differences in clinical responses to BCR-ABL TKIs in patients with Ph+ ALL and CML remain poorly understood, and cannot be exclusively attributed to mutations in the BCR-ABL kinase domain that impair drug binding.
Therefore, defining and countering the factors that underlie the transient response to BCR-ABL TKIs in patients with non-mutated BCR-ABL Ph+ ALL is critical for developing effective therapies that improve long-term survival. Moreover, contemporary medicine advocates co-treatment with agents of complementary mechanisms of action to counteract clinical drug resistance and improve outcomes. Therefore, there remains a need for therapies that are both safe, efficacious and complement targeted therapeutic agents for the treatment of cancer. These needs and other needs are satisfied by the present invention.